METHODS AND ANALYSIS: REKOVER is a phase-IV, multicountry, multicentre, prospective, real-world observational study. A total of 750 postsurgical and non-surgical patients (male and female, aged 18-80 years) will be recruited from 13 tertiary-care hospitals (15 sites) in Singapore, Thailand, the Philippines and Malaysia. All patients prescribed with TRAM/DKP FDC and willing to participate in the study will be enrolled. The recruitment duration for each site will be 6 months. The severity of pain will be collected using Numeric Pain Rating Scale through the treatment period from day 1 to day 5, while satisfaction with the treatment will be evaluated using Patient Global Evaluation Scale at the end of treatment. Any adverse event reported during the study duration will be recorded for safety analysis (up to day 6). The study data will be entered into the ClaimIt portal and mobile application (app) (ObvioHealth, USA). All the inpatient data will be entered into the portal by the study site and for outpatient it will be done by patients through an app.

BACKGROUND: CKD is associated with fluid excess that can be estimated by bioimpedance spectroscopy. We aimed to assess effects of sodium glucose co-transporter 2 inhibition on bioimpedance-derived "Fluid Overload" and adiposity in a CKD population.

METHODS: EMPA-KIDNEY was a double-blind placebo-controlled trial of empagliflozin 10 mg once daily in patients with CKD at risk of progression. In a substudy, bioimpedance measurements were added to the main trial procedures at randomization and at 2- and 18-month follow-up visits. The substudy's primary outcome was the study-average difference in absolute "Fluid Overload" (an estimate of excess extracellular water) analyzed using a mixed model repeated measures approach.

RESULTS: The 660 substudy participants were broadly representative of the 6609-participant trial population. Substudy mean baseline absolute "Fluid Overload" was 0.4±1.7 L. Compared with placebo, the overall mean absolute "Fluid Overload" difference among those allocated empagliflozin was -0.24 L (95% confidence interval [CI], -0.38 to -0.11), with similar sized differences at 2 and 18 months, and in prespecified subgroups. Total body water differences comprised between-group differences in extracellular water of -0.49 L (95% CI, -0.69 to -0.30, including the -0.24 L "Fluid Overload" difference) and a -0.30 L (95% CI, -0.57 to -0.03) difference in intracellular water. There was no significant effect of empagliflozin on bioimpedance-derived adipose tissue mass (-0.28 kg [95% CI, -1.41 to 0.85]). The between-group difference in weight was -0.7 kg (95% CI, -1.3 to -0.1).

CONCLUSIONS: In a broad range of patients with CKD, empagliflozin resulted in a sustained reduction in a bioimpedance-derived estimate of fluid overload, with no statistically significant effect on fat mass.

OBJECTIVE: The aim of this study is to investigate the effects of 3-month supplementation with oral probiotics on quality of life and inflammatory markers in women with primary dysmenorrhea.

DESIGN: Randomized placebo-controlled trial.

METHODS: A total of 72 patients (36 patients in each arm) were randomized to receive either oral sachets containing 5 billion colony-forming units each of Lactobacillus acidophilus BCMC (BCrobes Microbial Cells) 12130, Lactobacillus casei subsp BCMC 12313, Lactobacillus lactis BCMC 12451, Bifidobacterium bifidum BCMC 02290, Bifidobacterium longum BCMC 02120, and Bifidobacterium infantis BCMC 02129 each or placebo twice daily for 3 months. Main outcome measures were visual analog scale, verbal rating scale, physical and mental health scores using Short-Form 12-Item version 2 questionnaire, frequency of nonsteroidal anti-inflammatory drug use, and changes in inflammatory markers (interleukin-6, interleukin-8, and tumor necrosis factor alpha) before and after treatment.

RESULTS: There was no significant difference in the quality of life scores between the probiotic and placebo groups. Both groups showed significant improvement in pain (visual analog scale) and severity (verbal rating scale) scores but the probiotic group had much lower nonsteroidal anti-inflammatory drug use (odds ratio: 0.69, 95% confidence interval: 0.26-1.83) and better mental health scores (mean change: 6.5, p = 0.03 versus 6.1, p = 0.08) than the placebo group. There was a significant confounding effect of nonsteroidal anti-inflammatory drug use on quality of life scores. No significant difference was found in inflammatory cytokines.

CONCLUSION: Tested oral probiotics improved mental health and potentially reduced the use of nonsteroidal anti-inflammatory drugs; however, there was no significant change in inflammatory markers. Further research with a larger sample size is needed to confirm the findings.

METHODS: ALPHA is an ongoing, international, phase 3, randomised, double-blind, placebo-controlled trial evaluating danicopan as add-on therapy to ravulizumab or eculizumab. Eligible patients were adults (age ≥18 years) with PNH and clinically significant extravascular haemolysis (haemoglobin ≤9·5 g/dL; absolute reticulocyte count ≥120 × 109/L) on ravulizumab or eculizumab for at least 6 months. Patients were randomly assigned (2:1) to danicopan or placebo added to ravulizumab or eculizumab for 12 weeks using an interactive response technology system. Randomisation was stratified based on transfusion history, haemoglobin, and patients enrolled from Japan. The initial oral danicopan dose was 150 mg three times a day; escalation to 200 mg three times a day was permitted based on clinical response. The infusion dose level of eculizumab (every 2 weeks) ranged from 900 mg to 1500 mg, and for ravulizumab (monthly or every 8 weeks) ranged from 3000 mg to 3600 mg. The primary endpoint was change in haemoglobin concentration from baseline to week 12. Here we present the protocol-prespecified interim analysis, planned when approximately 75% of participants were randomly assigned to treatment and completed or discontinued at 12 weeks. This trial is registered with ClinicalTrials.gov (NCT04469465).

FINDINGS: Individuals were randomly assigned between Dec 16, 2020, and Aug 29, 2022. At data cutoff (June 28, 2022), 73 individuals were randomly assigned, received treatment, and were analysed for safety (danicopan, n=49; placebo, n=24). The protocol-prespecified interim efficacy analysis set included the first 63 participants (danicopan, n=42; placebo, n=21). At week 12, danicopan plus ravulizumab or eculizumab increased haemoglobin versus placebo plus ravulizumab or eculizumab (least squares mean [LSM] change from baseline: danicopan, 2·94 g/dL [95% CI 2·52 to 3·36]; placebo, 0·50 g/dL [-0·13 to 1·12]; LSM difference, 2·44 g/dL [1·69 to 3·20]; p<0·0001). Grade 3 adverse events in the danicopan group were increased alanine aminotransferase (two [4%] of 49 patients), leukopenia (one [2%]), neutropenia (two [4%]), cholecystitis (one [2%]), COVID-19 (one [2%]), increased aspartate aminotransferase (one [2%]), and increased blood pressure (one [2%]), and in the placebo group were anaemia (one [4%] of 24 patients), thrombocytopenia (one [4%]), and asthenia (one [4%]). The serious adverse events reported in the danicopan group were cholecystitis (one [2%] patient) and COVID-19 (one [2%]) and in the placebo group were anaemia and abdominal pain, both in one (4%) patient. There were no serious adverse events related to study drug or deaths reported in the study.

INTERPRETATION: These primary efficacy and safety results show that danicopan as add-on treatment to ravulizumab or eculizumab significantly improved haemoglobin concentrations at week 12 with no new safety concerns, suggesting an improved benefit-risk profile in patients with PNH and clinically significant extravascular haemolysis.

METHODS AND ANALYSIS: This 12-week randomised double-blind, placebo-controlled, parallel-group study aims to evaluate the efficacy of the standardised water extract of EL known as Physta in increasing the quality of life of perimenopausal and postmenopausal women. The study involves 150 women aged 40-55 years who score more than 61 on the Menopause-Specific Quality of Life (MENQOL) assessment. These participants will be randomised into three groups, receiving Physta at either 50 mg or 100 mg or a placebo. The outcomes measures include mood state, quality of life, fatigue, sleep quality, sexual function and pain score assessed using Profile of Mood State, MENQOL, Chalder Fatigue Scale, Pittsburgh Sleep Quality Index, Female Sexual Function Index and the Brief Pain Inventory questionnaires, respectively. The secondary outcome of the study includes full blood analysis, urine analysis, female reproductive hormone profiling, inflammatory and oxidative stress biomarkers analysis.

ETHICS AND DISSEMINATION: The research protocol of the study was reviewed and approved by the Research Ethics Committee of Universiti Kebangsaan Malaysia (UKM/PPI/111/8/JEP-2021-898). The findings will be disseminated to participants, healthcare professionals and researchers via conference presentations and peer-reviewed publications.

METHODS: This multicentre, randomised, placebo-controlled, phase 2b trial was done at 60 hospitals and clinics in 20 countries. Eligible study participants were aged between 12 and 75 years with a documented history of GPP as per the European Rare and Severe Psoriasis Expert Network criteria, with a history of at least two past GPP flares, and a GPP Physician Global Assessment (GPPGA) score of 0 or 1 at screening and random assignment. Patients were randomly assigned (1:1:1:1) to receive subcutaneous placebo, subcutaneous low-dose spesolimab (300 mg loading dose followed by 150 mg every 12 weeks), subcutaneous medium-dose spesolimab (600 mg loading dose followed by 300 mg every 12 weeks), or subcutaneous high-dose spesolimab (600 mg loading dose followed by 300 mg every 4 weeks) over 48 weeks. The primary objective was to demonstrate a non-flat dose-response curve on the primary endpoint, time to first GPP flare.

FINDINGS: From June 8, 2020, to Nov 23, 2022, 157 patients were screened, of whom 123 were randomly assigned. 92 were assigned to receive spesolimab (30 high dose, 31 medium dose, and 31 low dose) and 31 to placebo. All patients were either Asian (79 [64%] of 123) or White (44 [36%]). Patient groups were similar in sex distribution (76 [62%] female and 47 [38%] male), age (mean 40·4 years, SD 15·8), and GPP Physician Global Assessment score. A non-flat dose-response relationship was established on the primary endpoint. By week 48, 35 patients had GPP flares; seven (23%) of 31 patients in the low-dose spesolimab group, nine (29%) of 31 patients in the medium-dose spesolimab group, three (10%) of 30 patients in the high-dose spesolimab group, and 16 (52%) of 31 patients in the placebo group. High-dose spesolimab was significantly superior versus placebo on the primary outcome of time to GPP flare (hazard ratio [HR]=0·16, 95% CI 0·05-0·54; p=0·0005) endpoint. HRs were 0·35 (95% CI 0·14-0·86, nominal p=0·0057) in the low-dose spesolimab group and 0·47 (0·21-1·06, p=0·027) in the medium-dose spesolimab group. We established a non-flat dose-response relationship for spesolimab compared with placebo, with statistically significant p values for each predefined model (linear p=0·0022, emax1 p=0·0024, emax2 p=0·0023, and exponential p=0·0034). Infection rates were similar across treatment arms; there were no deaths and no hypersensitivity reactions leading to discontinuation.

INTERPRETATION: High-dose spesolimab was superior to placebo in GPP flare prevention, significantly reducing the risk of a GPP flare and flare occurrence over 48 weeks. Given the chronic nature of GPP, a treatment for flare prevention is a significant shift in the clinical approach, and could ultimately lead to improvements in patient morbidity and quality of life.

METHODS AND ANALYSIS: This is double-blind randomised controlled trial, with parallel group, concealed allocation, blinding of patients and assessors, and intention-to-treat analysis. 240 adult participants who had median sternotomy from eight hospitals in Malaysia will be recruited. Sample size calculations were based on the unsupported upper limb test. All participants will be randomised to receive either standard or early supervised incremental resistance training. The primary outcomes are upper limb function and pain. The secondary outcomes will be functional capacity, multidomain recovery (physical and psychological), length of hospital stay, incidence of respiratory complications and quality of life. Descriptive statistics will be used to summarise data. Data will be analysed using the intention-to-treat principle. The primary hypothesis will be examined by evaluating the change from baseline to the 4-week postoperative time point in the intervention arm compared with the usual care arm. For all tests to be conducted, a p value of <0.05 (two tailed) will be considered statistically significant, and CIs will be reported. The trial is currently recruiting participants.

ETHICS AND DISSEMINATION: The study was approved by a central ethical committee as well as the local Research Ethics Boards of the participating sites (UKM:JEP-2019-654; Ministry of Health: NMMR-50763; National Heart Centre: IJNREC/501/2021). Approval to start was given prior to the recruitment of participants commencing at any sites. Process evaluation findings will be published in peer-reviewed journals and presented at relevant academic conferences.

INTRODUCTION: SCF has been reported to improve calcium absorption. We investigated the long-term effect of SCF and calcium on bone indices of healthy preadolescent children aged 9-11 years old.

METHODS: In a double-blind, randomised, parallel arm study, 243 participants were randomised into four groups: placebo, 12-g SCF, 600-mg calcium lactate gluconate (Ca) and 12-g SCF + 600-mg calcium lactate gluconate (SCF + Ca). Total body bone mineral content (TBBMC) and total body bone mineral density (TBBMD) were measured using dual-energy X-ray absorptiometry at baseline, 6 and 12 months.

METHODS: The study is a randomised double-blind placebo-controlled phase-II single-site clinical trial conducted in Perth, Australia. The target sample is to recruit 240 participants diagnosed with chronic frequent episodic migraines between 18 and 80 years of age. Participants will be randomised to one of four treatment groups for 14 weeks (placebo induction for 2 weeks, followed by 12 weeks on one of the respective treatment arms): placebo, L-arginine, AGE, or a combination of L-arginine and AGE. The doses of L-arginine and AGE are 1.5 g and 1 g daily, respectively. The primary outcome is to assess migraine response using change in migraine frequency and intensity between baseline and 12 weeks. Secondary outcomes include the impact of L-arginine and/or AGE on photosensitivity, retinal vessel changes, and blood biomarker concentrations of vascular tone, following a 12-week intervention.

DISCUSSION: The protocol describes the oral administration of 2 nutraceutical-based interventions as possible prophylactic treatments for chronic frequent episodic migraines, with potential for direct clinical translation of outcomes. Potential limitations of the study include the fixed-dose design of each treatment arm and that in vivo neuroimaging methods, such as magnetic resonance imaging (MRI), will not be conducted to determine putative cerebro-vasodilatory changes to coincide with the outcome measures. Dose-response studies may be indicated.

METHODS: In a double-blind, phase III trial, 453 patients with advanced HCC and progression during or after treatment with or intolerance to sorafenib or oxaliplatin-based chemotherapy were randomly assigned in a 2:1 ratio to receive pembrolizumab (200 mg) or placebo once every 3 weeks for ≤ 35 cycles plus best supportive care. The primary end point was overall survival (one-sided significance threshold, P = .0193 [final analysis]). Secondary end points included progression-free survival (PFS) and objective response rate (ORR; one-sided significance threshold, P = .0134 and .0091, respectively [second interim analysis]; RECIST version 1.1, by blinded independent central review).

RESULTS: Median overall survival was longer in the pembrolizumab group than in the placebo group (14.6 v 13.0 months; hazard ratio for death, 0.79; 95% CI, 0.63 to 0.99; P = .0180). Median PFS was also longer in the pembrolizumab group than in the placebo group (2.6 v 2.3 months; hazard ratio for progression or death, 0.74; 95% CI, 0.60 to 0.92; P = .0032). ORR was greater in the pembrolizumab group (12.7% [95% CI, 9.1 to 17.0]) than in the placebo group (1.3% [95% CI, 0.2 to 4.6]; P < .0001). Treatment-related adverse events occurred in 66.9% of patients (grade 3, 12.0%; grade 4, 1.3%; grade 5, 1.0%) in the pembrolizumab group and 49.7% of patients (grade 3, 5.9%; grade 4, 0%; grade 5, 0%) in the placebo group.

MATERIALS AND METHODS: A double-blind, parallel, randomized control trial was conducted with 219 university students who were divided into three trial groups using block randomization: CPC, CHX and placebo groups. Clinical oral examinations to assess dental plaque accumulation (modified Quigley-Hein Plaque Index), gingival health (Löe and Silness Gingival Index) and tooth staining (modified Lobene Stain Index) were performed at baseline and at 6 weeks.

RESULTS: Plaque and gingivitis scores were not significantly different among participants at baseline. After 6 weeks, plaque and gingivitis scores between the CPC and placebo groups and between the CHX and placebo groups were found to be significantly different. However, there was no significant difference between the CPC and CHX groups. The staining scores of participants in the CPC group were lower than those in the CHX group, but the difference was not significant. Taste alteration and numbness were more common among participants in the CHX group than in the CPC group. No significant difference in the perception of a burning sensation was observed.

METHODS AND RESULTS: This randomized trial tested vitamin D 60,000 IU monthly in 5670 participants without vascular disease but at increased CV risk. The primary outcome was fracture. The secondary outcome was the composite of CV death, myocardial infarction stroke, cancer, fracture or fall. Death was a pre-specified outcome. Mean age was 63.9 years, and 3005 (53.0%) were female. 3034 (53.5%) participants resided in South Asia, 1904 (33.6%) in South East Asia, 480 (8.5%) in South America, and 252 (4.4%) in other regions. Mean follow-up was 4.6 years. A fracture occurred in 20 participants (0.2 per 100 person years) assigned to vitamin D, and 19 (0.1 per 100 person years) assigned to placebo (HR 1.06, 95% CI 0.57-1.99, p-value = 0.86). The secondary outcome occurred in 222 participants (1.8 per 100 person years) assigned to vitamin D, and 198 (1.6 per 100 person years) assigned to placebo (HR 1.13, 95% CI 0.93-1.37, p = 0.22). 172 (1.3 per 100 person years) participants assigned to vitamin D died, compared with 135 (1.0 per 100 person years) assigned to placebo (HR 1.29, 95% CI 1.03-1.61, p = 0.03).

CONCLUSION: In a population predominantly from South Asia, South East Asia and South America, high-dose vitamin D did not reduce adverse skeletal or non-skeletal outcomes. Higher mortality was observed in the vitamin D group.

METHODS AND ANALYSIS: Initially, during Phase I of the study, the serum level of IL-1β, IL-6 and TNF-α; ERP changes in the EEG and fecal microbiota content will be compared between 120 AUD patients and 120 healthy controls. Subsequently in Phase II of the study, 120 AUD patients will be randomized by stratified permuted block randomization into the probiotic, ACT and placebo groups in a 1:1:1 ratio. Participants in the probiotic and placebo groups will be administered one sachet per day of Lactobacillus spp. probiotic and placebo, respectively for 12 weeks. While those in the ACT group will receive one session per week of ACT for 8 weeks. Outcome measures will be administered at four timepoints, such as t0 = baseline assessment prior to intervention, t1 = 8 weeks after intervention began, t2 = 12 weeks after intervention and t3 = 24 weeks after intervention. Primary outcomes are the degrees of alcohol craving, alcohol withdrawal during abstinence and AUD. Secondary outcomes to be assessed are the severity of co-morbid depression and anxiety symptoms; the serum levels of IL-1β, IL-6 and TNF-α; changes in ERP and fecal microbiota content.