Metformin for the prevention of diabetes among people with HIV and either impaired fasting glucose or impaired glucose tolerance (prediabetes) in Tanzania: a Phase II randomised placebo-controlled trial.
AIMS/HYPOTHESIS In sub-Saharan Africa (SSA), 5% of adults are living with type 2 diabetes and this is rising sharply, with a greater increase among people with HIV. Evidence on the efficacy of prevention strategies in this cohort is scarce. We conducted a Phase II double-blind placebo-controlled trial that aimed to determine the impact of metformin on blood glucose levels among people with prediabetes (defined as impaired fasting glucose [IFG] and/or impaired glucose tolerance [IGT]) and HIV in SSA. METHODS Adults (≥18 years old) who were stable in HIV care and found to have prediabetes (IFG and/or IGT) and who were attending hospitals in Dar es Salaam, Tanzania, were randomised to receive sustained-release metformin, 2000 mg daily, or matching placebo between 4 November 2019 and 21 July 2020. Randomisation used permuted blocks. Allocation was concealed in the trial database and made visible only to the Chief Pharmacist after consent was taken. All participants, research and clinical staff remained blinded to the allocation. Participants were provided with information on diet and lifestyle and had access to various health information following the start of the coronavirus disease 2019 (COVID-19) pandemic. Participants were followed up for 12 months. The primary outcome measure was capillary blood glucose measured 2 h following a 75 g glucose load. Analyses were by intention-to-treat. RESULTS In total, 364 participants (182 in each arm) were randomised to the metformin or placebo group. At enrolment, in the metformin and placebo arms, mean fasting glucose was 6.37 mmol/l (95% CI 6.23, 6.50) and 6.26 mmol/l (95% CI 6.15, 6.36), respectively, and mean 2 h glucose levels following a 75 g oral glucose load were 8.39 mmol/l (95% CI 8.22, 8.56) and 8.24 mmol/l (95% CI 8.07, 8.41), respectively. At the final assessment at 12 months, 145/182 (79.7%) individuals randomised to metformin compared with 158/182 (86.8%) randomised to placebo indicated that they had taken >95% of their medicines in the previous 28 days (p=0.068). At this visit, in the metformin and placebo arms, mean fasting glucose levels were 6.17 mmol/l (95% CI 6.03, 6.30) and 6.30 mmol/l (95% CI 6.18, 6.42), respectively, and mean 2 h glucose levels following a 75 g oral glucose load were 7.88 mmol/l (95% CI 7.65, 8.12) and 7.71 mmol/l (95% CI 7.49, 7.94), respectively. Using a linear mixed model controlling for respective baseline values, the mean difference between the metformin and placebo group (metformin-placebo) was -0.08 mmol/l (95% CI -0.37, 0.20) for fasting glucose and 0.20 mmol/l (95% CI -0.17, 0.58) for glucose levels 2 h post a 75 g glucose load. Weight was significantly lower in the metformin arm than in the placebo arm: using the linear mixed model adjusting for baseline values, the mean difference in weight was -1.47 kg (95% CI -2.58, -0.35). In total, 16/182 (8.8%) individuals had a serious adverse event (Grade 3 or Grade 4 in the Division of Acquired Immunodeficiency Syndrome [DAIDS] adverse event grading table) or died in the metformin arm compared with 18/182 (9.9%) in the placebo arm; these events were either unrelated to or unlikely to be related to the study drugs. CONCLUSIONS/INTERPRETATION Blood glucose decreased over time in both the metformin and placebo arms during the trial but did not differ significantly between the arms at 12 months of follow up. Metformin therapy was found to be safe for use in individuals with HIV and prediabetes. A larger trial with longer follow up is needed to establish if metformin can be safely used for the prevention of diabetes in people who have HIV. TRIAL REGISTRATION The trial is registered on the International Standard Randomised Controlled Trial Number (ISRCTN) registry ( www.isrctn.com/ ), registration number: ISCRTN76157257. FUNDING This research was funded by the National Institute for Health Research using UK aid from the UK Government to support global health research.
Efficacy and safety of luspatercept versus epoetin alfa in erythropoiesis-stimulating agent-naive, transfusion-dependent, lower-risk myelodysplastic syndromes (COMMANDS): interim analysis of a phase 3, open-label, randomised controlled trial.
Lancet (London, England). 2023;(10399):373-385
BACKGROUND Erythropoiesis-stimulating agents (ESAs) are the standard-of-care treatment for anaemia in most patients with lower-risk myelodysplastic syndromes but responses are limited and transient. Luspatercept promotes late-stage erythroid maturation and has shown durable clinical efficacy in patients with lower-risk myelodysplastic syndromes. In this study, we report the results of a prespecified interim analysis of luspatercept versus epoetin alfa for the treatment of anaemia due to lower-risk myelodysplastic syndromes in the phase 3 COMMANDS trial. METHODS The phase 3, open-label, randomised controlled COMMANDS trial is being conducted at 142 sites in 26 countries. Eligible patients were aged 18 years or older, had a diagnosis of myelodysplastic syndromes of very low risk, low risk, or intermediate risk (per the Revised International Prognostic Scoring System), were ESA-naive, and required red blood cell transfusions (2-6 packed red blood cell units per 8 weeks for ≥8 weeks immediately before randomisation). Integrated response technology was used to randomly assign patients (1:1, block size 4) to luspatercept or epoetin alfa, stratified by baseline red blood cell transfusion burden (<4 units per 8 weeks vs ≥4 units per 8 weeks), endogenous serum erythropoietin concentration (≤200 U/L vs >200 to <500 U/L), and ring sideroblast status (positive vs negative). Luspatercept was administered subcutaneously once every 3 weeks starting at 1·0 mg/kg body weight with possible titration up to 1·75 mg/kg. Epoetin alfa was administered subcutaneously once a week starting at 450 IU/kg body weight with possible titration up to 1050 IU/kg (maximum permitted total dose of 80 000 IU). The primary endpoint was red blood cell transfusion independence for at least 12 weeks with a concurrent mean haemoglobin increase of at least 1·5 g/dL (weeks 1-24), assessed in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study treatment. The COMMANDS trial was registered with ClinicalTrials.gov, NCT03682536 (active, not recruiting). FINDINGS Between Jan 2, 2019 and Aug 31, 2022, 356 patients were randomly assigned to receive luspatercept (178 patients) or epoetin alfa (178 patients), comprising 198 (56%) men and 158 (44%) women (median age 74 years [IQR 69-80]). The interim efficacy analysis was done for 301 patients (147 in the luspatercept group and 154 in the epoetin alfa group) who completed 24 weeks of treatment or discontinued earlier. 86 (59%) of 147 patients in the luspatercept group and 48 (31%) of 154 patients in the epoetin alfa group reached the primary endpoint (common risk difference on response rate 26·6; 95% CI 15·8-37·4; p<0·0001). Median treatment exposure was longer for patients receiving luspatercept (42 weeks [IQR 20-73]) versus epoetin alfa (27 weeks [19-55]). The most frequently reported grade 3 or 4 treatment-emergent adverse events with luspatercept (≥3% patients) were hypertension, anaemia, dyspnoea, neutropenia, thrombocytopenia, pneumonia, COVID-19, myelodysplastic syndromes, and syncope; and with epoetin alfa were anaemia, pneumonia, neutropenia, hypertension, iron overload, COVID-19 pneumonia, and myelodysplastic syndromes. The most common suspected treatment-related adverse events in the luspatercept group (≥3% patients, with the most common event occurring in 5% patients) were fatigue, asthenia, nausea, dyspnoea, hypertension, and headache; and none (≥3% patients) in the epoetin alfa group. One death after diagnosis of acute myeloid leukaemia was considered to be related to luspatercept treatment (44 days on treatment). INTERPRETATION In this interim analysis, luspatercept improved the rate at which red blood cell transfusion independence and increased haemoglobin were achieved compared with epoetin alfa in ESA-naive patients with lower-risk myelodysplastic syndromes. Long-term follow-up and additional data will be needed to confirm these results and further refine findings in other subgroups of patients with lower-risk myelodysplastic syndromes, including non-mutated SF3B1 or ring sideroblast-negative subgroups. FUNDING Celgene and Acceleron Pharma.
Pathogen reduction with methylene blue does not have an impact on the clinical effectiveness of COVID-19 convalescent plasma.
Vox sanguinis. 2023;(4):296-300
BACKGROUND AND OBJECTIVES There is a concern about a possible deleterious effect of pathogen reduction (PR) with methylene blue (MB) on the function of immunoglobulins of COVID-19 convalescent plasma (CCP). We have evaluated whether MB-treated CCP is associated with a poorer clinical response compared to other inactivation systems at the ConPlas-19 clinical trial. MATERIALS AND METHODS This was an ad hoc sub-study of the ConPlas-19 clinical trial comparing the proportion of patients transfused with MB-treated CCP who had a worsening of respiration versus those treated with amotosalen (AM) or riboflavin (RB). RESULTS One-hundred and seventy-five inpatients with SARS-CoV-2 pneumonia were transfused with a single CCP unit. The inactivation system of the CCP units transfused was MB in 90 patients (51.4%), RB in 60 (34.3%) and AM in 25 (14.3%). Five out of 90 patients (5.6%) transfused with MB-treated CCP had worsening respiration compared to 9 out of 85 patients (10.6%) treated with alternative PR methods (p = 0.220). Of note, MB showed a trend towards a lower rate of respiratory progressions at 28 days (risk ratio, 0.52; 95% confidence interval, 0.18-1.50). CONCLUSION Our data suggest that MB-treated CCP does not provide a worse clinical outcome compared to the other PR methods for the treatment of COVID-19.
Molnupiravir for the treatment of COVID-19 in immunocompromised participants: efficacy, safety, and virology results from the phase 3 randomized, placebo-controlled MOVe-OUT trial.
PURPOSE Immunocompromised patients have a potentially increased risk for progression to severe COVID-19 and prolonged replication of SARS-CoV-2. This post hoc analysis examined outcomes among immunocompromised participants in the MOVe-OUT trial. METHODS In phase 3 of MOVe-OUT, non-hospitalized at-risk adults with mild-to-moderate COVID-19 were randomized to receive molnupiravir 800 mg or placebo twice daily for 5 days. Immunocompromised participants were identified based on prior/concomitant medications and/or medical history. All-cause hospitalization/death, adverse events, SARS-CoV-2 titers, infectivity, and RNA sequences were compared between immunocompromised participants who received molnupiravir or placebo and with non-immunocompromised participants. RESULTS Fifty-five of 1408 participants were considered immunocompromised. Compared to placebo, fewer molnupiravir-treated immunocompromised participants were hospitalized/died through Day 29 (22.6% [7/31] vs. 8.3% [2/24]), with fewer adverse events (45.2% [14/31] vs. 25.0% [6/24]). A larger mean change from baseline in SARS-CoV-2 RNA was observed with molnupiravir compared to placebo in non-immunocompromised participants (least squares mean [LSM] difference Day 5: - 0.31, 95% confidence interval [CI] - 0.47 to - 0.15), while the mean change was comparable between treatment groups in immunocompromised participants (LSM difference Day 5: 0.23, 95% CI - 0.71 to 1.17). Molnupiravir treatment was associated with increased clearance of infectious virus. Increased errors in viral nucleotide sequences in post-baseline samples compared to placebo support molnupiravir's mechanism of action and were not associated with observation of novel treatment-emergent amino acid substitutions in immunocompromised participants. CONCLUSION Although the study population was small, these data suggest that molnupiravir treatment for mild-to-moderate COVID-19 in non-hospitalized immunocompromised adults is efficacious and safe and quickly reduces infectious SARS-CoV-2. GOV REGISTRATION NUMBER NCT04575597.
A first-in-human phase 1 study of simnotrelvir, a 3CL-like protease inhibitor for treatment of COVID-19, in healthy adult subjects.
European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. 2023;:106598
Safe and efficacious antiviral therapeutics are in urgent need for the treatment of coronavirus disease 2019. Simnotrelvir is a selective 3C-like protease inhibitor that can effectively inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We evaluated the safety, tolerability, and pharmacokinetics of dose escalations of simnotrelvir alone or with ritonavir (simnotrelvir or simnotrelvir/ritonavir) in healthy subjects, as well as the food effect (ClinicalTrials.gov Identifier: NCT05339646). The overall incidence of adverse events (AEs) was 22.2% (17/72) and 6.3% (1/16) in intervention and placebo groups, respectively. The simnotrelvir apparent clearance was 135-369 L/h with simnotrelvir alone, and decreased significantly to 19.5-29.8 L/h with simnotrelvir/ritonavir. The simnotrelvir exposure increased in an approximately dose-proportional manner between 250 and 750 mg when co-administered with ritonavir. After consecutive twice daily dosing of simnotrelvir/ritonavir, simnotrelvir had a low accumulation index ranging from 1.39 to 1.51. The area under the curve of simnotrelvir increased 44.0 % and 47.3 % respectively, after high fat and normal diet compared with fasted status. In conclusion, simnotrelvir has adequate safety and tolerability. Its pharmacokinetics indicated a trough concentration above the level required for 90 % inhibition of SARS-CoV-2 in vitro at 750 mg/100 mg simnotrelvir/ritonavir twice daily under fasted condition, supporting further development using this dosage as the clinically recommended dose regimen.
Effects of a Multi-Professional Intervention on Mental Health of Middle-Aged Overweight Survivors of COVID-19: A Clinical Trial.
International journal of environmental research and public health. 2023;(5)
The present study aimed to investigate the effects of a multi-professional intervention model on the mental health of middle-aged, overweight survivors of COVID-19. A clinical trial study with parallel groups and repeated measures was conducted. For eight weeks, multi-professional interventions were conducted (psychoeducation, nutritional intervention, and physical exercises). One hundred and thirty-five overweight or obese patients aged 46.46 ± 12.77 years were distributed into four experimental groups: mild, moderate, severe COVID, and control group. The instruments were used: mental health continuum-MHC, revised impact scale-IES-r, generalized anxiety disorder-GAD-7, and Patient health questionnaire PHQ-9, before and after eight weeks. The main results indicated only a time effect, with a significant increase in global MHC scores, emotional well-being, social well-being, and psychological well-being, as well as detected a significant reduction in global IES-R scores, intrusion, avoidance, and hyperarousal, in addition to a reduction in GAD-7 and PHQ-9 scores (p < 0.05). In conclusion, it was possible to identify those psychoeducational interventions that effectively reduced anxiety, depression, and post-traumatic stress symptoms in post-COVID-19 patients, regardless of symptomatology, in addition to the control group. However, moderate and severe post-COVID-19 patients need to be monitored continuously since the results of these groups did not follow the response pattern of the mild and control groups.
Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata over 52 Weeks of Continuous Therapy in Two Phase III Trials (BRAVE-AA1 and BRAVE-AA2).
American journal of clinical dermatology. 2023;(3):443-451
BACKGROUND The oral Janus kinase (JAK) inhibitor baricitinib has demonstrated efficacy for severe alopecia areata (AA) over 36 weeks. There are limited data on the longer-term treatment of AA. OBJECTIVE The aim of this study was to evaluate the efficacy and safety of baricitinib for AA in adults with ≥50% scalp hair loss through 52 weeks of continuous therapy in two phase III trials (BRAVE-AA1 and BRAVE-AA2). METHODS Patients randomized to baricitinib at baseline in BRAVE-AA1 (N = 465) and BRAVE-AA2 (N = 390) retained their treatment allocation through Week 52. Efficacy outcomes included the proportion of patients achieving a Severity of Alopecia Tool (SALT) score ≤ 20 (≤ 20% scalp hair loss). Data were censored after permanent treatment discontinuation or if collected remotely due to the coronavirus disease 2019 (COVID-19) pandemic. RESULTS Response rates for hair regrowth increased over the 52-week period. Of patients treated with baricitinib 4 mg and 2 mg, respectively, 40.9% and 21.2% in BRAVE-AA1 and 36.8% and 24.4% in BRAVE-AA2 achieved a SALT score ≤ 20 at Week 52. The most frequent treatment-emergent adverse events included upper respiratory tract infection, headache, nasopharyngitis, acne, urinary tract infection, creatine phosphokinase elevation, and COVID-19 infection. LIMITATION There were no comparisons with placebo. CONCLUSION Efficacy of baricitinib for adults with severe AA continuously improved over 52 weeks, indicating that long-term treatment may be necessary to observe maximum clinical benefit. There were no new safety signals. CLINICALTRIALS REGISTRATION ClinicalTrials.gov NCT03570749 and NCT03899259. Efficacy and Safety of Baricitinib in Patients with Severe Alopecia Areata: Week-52 Results from BRAVE-AA1 and BRAVE-AA2.
Effects of a family-based lifestyle intervention on co-physical activity and other health-related outcomes of fathers and their children: the 'Run Daddy Run' intervention.
BMC public health. 2023;(1):342
BACKGROUND Fathers are important in establishing healthy behaviors in their children, but are rarely engaged in lifestyle programs. Focusing on physical activity (PA) of both fathers and their children by engaging them together in PA (i.e. "co-PA") is therefore a promising novel strategy for interventions. The study aim was to investigate the effect of the 'Run Daddy Run' on co-PA and PA of fathers and their children, and secondary outcomes such as weight status and sedentary behaviour (SB). METHODS This study is a non-randomized controlled trial (nRCT), including 98 fathers and one of their 6 to 8 years old children (intervention = 35, control = 63). The intervention was implemented over a 14-week period, and consisted of six (inter)active father-child sessions and an online component. Due to COVID-19, only 2/6 sessions could be implemented as planned, the remaining sessions were delivered online. In November 2019-January 2020 pre-test measurements took place, and post-test measurements in June 2020. Additional follow-up test was conducted in November 2020. PA (i.e. LPA, MPA, VPA and volume) of fathers and children were objectively measured using accelerometry, co-PA and the secondary outcomes were questioned using an online questionnaire. RESULTS Significant intervention effects were found for co-PA (+ 24 min./day in the intervention compared to the control group, p = 0.002), and MPA of the father (+ 17 min./day, p = 0.035). For children, a significant increase in LPA (+ 35 min./day, p < 0.001) was found. However, an inverse intervention effect was found for their MPA and VPA (-15 min./day, p = 0.005 and - 4 min./day, p = 0.002, respectively). Also decreases in fathers' and children's SB were found (-39 min./day, p = 0.022 and - 40 min./day, p = 0.003, respectively), but no changes in weight status, the father-child relationship, and the PA-family health climate (all p > 0.05). CONCLUSION The Run Daddy Run intervention was able to improve co-PA, MPA of fathers and LPA of children, and decreasing their SB. Inverse intervention effects were however found for MPA and VPA of children. These results are unique given their magnitude and clinical relevance. Targeting fathers together with their children might be a novel and potential intervention strategy to improve overall physical activity levels, however, further efforts should however be made to target children's MPA and VPA. Last, replicating these findings in a randomized controlled trial (RCT) is recommended for future research. TRIAL REGISTRATION NUMBER This study is registered as a clinical trial (clinicaltrials.gov, ID number: NCT04590755, date: 19/10/2020).
Utility of mouth rinses with povidone-iodine and hydrogen peroxide in patients with COVID-19.
Enfermedades infecciosas y microbiologia clinica (English ed.). 2023;(3):173-175
INTRODUCTION Povidone-iodine and hydrogen peroxide could be effective in against SARS-CoV-2. METHODS A "non-interventional trial" in 88 patients (43±17 yrs., 55% men) with SARS-CoV-2 in nasopharyngeal swabs (RT-PCR). 31 received mouth rinses/gargling with povidone-iodine (every 8h, two consecutive days), 17 with mouth rinses/gargling of hydrogen peroxide, and 40 controls. Were repeated PCR in 3, 11 and 17 days. RESULTS After intervention the viral load (Log10 copies/ml) remained similar in povidone-iodine (4.3±2.7 copies/ml), hydrogen peroxide (4.6±2.9 copies/ml; p=0.40) and controls (4.4±3.0 copies/ml). The percentage of patients with a negative result in the second PCR was 27% in povidone-iodine group, 23% in hydrogen peroxide and 32% in controls; in the third PCR, 62%, 54% y 58% respectively; and in the fourth PCR, 81%, 75% y 81%. CONCLUSION Our results do not support the clinical usefulness of mouth rinses/gargling with povidone-iodine or hydrogen peroxide in patients with COVID-19.
Additive benefit of rehabilitation on physical status, symptoms and mental health after hospitalisation for severe COVID-19 pneumonia.
BMJ open respiratory research. 2023;(1)
INTRODUCTION The potential additive benefits of rehabilitation beyond spontaneous recovery post-COVID-19 currently remain unknown. METHODS In this prospective, interventional, non-randomised parallel assignment two-arm study, we investigated the effects of an 8-week rehabilitation programme (Rehab, n=25) added to usual care (UC) versus UC (n=27) on respiratory symptoms, fatigue, functional capacity, mental health and health-related quality of life in patients with COVID-19 pneumonia, 6-8 weeks post-hospital discharge. The rehabilitation programme included exercise, education, dietary and psychological support. Patients with chronic obstructive pulmonary disease, respiratory and heart failure were excluded from the study. RESULTS At baseline, groups were not different in mean age (56 years), gender (53% female), intensive care unit admission (61%), intubation (39%), days of hospitalisation (25), number of symptoms (9) and number of comorbidities (1.4). Baseline evaluation was conducted at median (IQR) 76 (27) days after symptoms onset. Groups were not different regarding baseline evaluation outcomes. At 8 weeks, Rehab showed significantly greater improvement in COPD Assessment Test by a mean±SEM (95% CI) 7.07±1.36 (4.29-9.84), p <0.001 and all three fatigue questionnaires: Chalder-Likert: 5.65±1.27 (3.04-8.25), p <0.001; bimodal: 3.04±0.86 (1.28-4.79), p=0.001; Functional Assessment of Chronic Illness Therapy: 6.37±2.09 (2.08-10.65), p=0.005 and Fatigue Severity Scale: 1.36±0.433 (0.47-2.25), p=0.004. At 8 weeks rehab also showed significantly greater improvment in Short Physical Performance Battery: 1.13±0.33 (0.46-1.79), p=0.002; Hospital Anxiety and Depression Scale (HADS) Anxiety: 2.93±1.01 (0.67-5.18), p=0.013; Beck Depression Inventory: 7.81±3.07 (1.52-14.09), p=0.017; Montreal Cognitive Assessment: 2.83±0.63 (1.5-4.14), p <0.001; EuroQol (EQ-5D-5L) Utility Index: 0.21±0.05 (0.1-0.32), p=0.001 and Visual Analogue Scale: 6.57±3.21 (0.2-13.16), p=0.043. Both groups significantly improved 6-min walking distance by approximately 60 m and pulmonary function measures, whereas post-traumatic stress disorder measurement IES-R (Impact of Event Scale, Revised) and HADS-Depression score were not different between groups at 8 weeks. A 16% attrition rate was observed in the rehabilitation group exhibiting a threefold increase in training workload. There were no adverse effects reported during exercise training. DISCUSSION These findings highlight the added value of rehabilitation post-COVID-19 to amplify the natural course of physical and mental recovery that otherwise would remain incomplete with UC.