-
American Journal of Respiratory and... Mar 2021In the phase III, 52-week ETHOS (Efficacy and Safety of Triple Therapy in Obstructive Lung Disease) trial in chronic obstructive pulmonary disease (COPD) (NCT02465567),... (Randomized Controlled Trial)
Randomized Controlled Trial
Reduced All-Cause Mortality in the ETHOS Trial of Budesonide/Glycopyrrolate/Formoterol for Chronic Obstructive Pulmonary Disease. A Randomized, Double-Blind, Multicenter, Parallel-Group Study.
In the phase III, 52-week ETHOS (Efficacy and Safety of Triple Therapy in Obstructive Lung Disease) trial in chronic obstructive pulmonary disease (COPD) (NCT02465567), triple therapy with budesonide/glycopyrrolate/formoterol fumarate (BGF) significantly reduced all-cause mortality compared with glycopyrrolate/formoterol fumarate (GFF). However, 384 of 8,509 patients were missing vital status at Week 52 in the original analyses. To assess the robustness of the ETHOS mortality findings after additional data retrieval for patients missing Week 52 vital status in the original analyses. Patients with moderate to very severe COPD and prior history of exacerbation received twice-daily dosing with 320/18/9.6 μg of BGF (BGF 320), 160/18/9.6 μg of BGF (BGF 160), 18/9.6 μg of GFF, or 320/9.6 μg of budesonide/formoterol fumarate (BFF) (all delivered via a single metered-dose Aerosphere inhaler). Time to death (all-cause) was a prespecified secondary endpoint. In the final retrieved dataset, which included Week 52 vital status for 99.6% of the intent-to-treat population, risk of death with BGF 320 was significantly lower than GFF (hazard ratio, 0.51; 95% confidence interval, 0.33-0.80; unadjusted = 0.0035). There were no significant differences in mortality when comparing BGF 320 with BFF (hazard ratio, 0.72; 95% confidence interval, 0.44-1.16; = 0.1721), nor were significant differences observed when comparing BGF 160 against either dual comparator. Results were similar when the first 30, 60, or 90 days of treatment were excluded from the analysis. Deaths from cardiovascular causes occurred in 0.5%, 0.8%, 1.4%, and 0.5% of patients in the BGF 320, BGF 160, GFF, and BFF groups, respectively. Using final retrieved vital status data, triple therapy with BGF 320 reduced the risk of death compared with GFF, but was not shown to significantly reduce the risk of death compared with BFF, in patients with COPD. Triple therapy containing a lower dose of inhaled corticosteroid (BGF 160) was not shown to significantly reduce the risk of death compared with the dual therapy comparators.
Topics: Aged; Bronchodilator Agents; Budesonide; Cause of Death; Double-Blind Method; Drug Therapy, Combination; Female; Forced Expiratory Volume; Formoterol Fumarate; Glucocorticoids; Glycopyrrolate; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Mortality; Muscarinic Antagonists; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index
PubMed: 33252985
DOI: 10.1164/rccm.202006-2618OC -
Journal of Clinical Hypertension... Sep 2023Hypertension is the leading cause of death worldwide, affecting 1.4 billion people. Treatment options include the widely used calcium channel blockers, among which... (Review)
Review
Hypertension is the leading cause of death worldwide, affecting 1.4 billion people. Treatment options include the widely used calcium channel blockers, among which amlodipine, a dihydropyridine, has unique characteristics that distinguish it from other drugs within this class. This review aims to provide an updated overview of the evidence supporting the use of amlodipine over the past 30 years and highlights its cardiovascular benefits in current hypertension management. Amlodipine has low renal clearance (7 mL/min/mg) and long half-life (35-50 h) and duration of action, which allows it to sustain its anti-hypertensive effect for more than 24 h following a single dose. Additionally, blood pressure (BP) control is maintained even when a dose has been missed, providing continuous protection in case of incidental noncompliance. It has proven to reduce BP variability and successfully lower BP. Amlodipine also controls BP in patients with a systolic/diastolic BP of 130/80 mm Hg or higher, diabetes, or chronic kidney disease without worsening glycemic or kidney function. Additionally, amlodipine is a wise choice for older adults due to its ability to control BP and protect against stroke and myocardial infarction. Side effects of amlodipine include edema, palpitations, dizziness, and flushing, which are more common with the higher dose of 10 mg. Amlodipine is cost effective and predicted to be cost saving when compared with usual care.
Topics: Humans; Aged; Amlodipine; Hypertension; Antihypertensive Agents; Calcium Channel Blockers; Blood Pressure
PubMed: 37551050
DOI: 10.1111/jch.14709 -
Journal of Medical Internet Research Feb 2022Nonadherence to medication in tuberculosis (TB) hampers optimal treatment outcomes. Digital health technology (DHT) seems to be a promising approach to managing problems... (Review)
Review
BACKGROUND
Nonadherence to medication in tuberculosis (TB) hampers optimal treatment outcomes. Digital health technology (DHT) seems to be a promising approach to managing problems of nonadherence to medication and improving treatment outcomes.
OBJECTIVE
This paper systematically reviews the effect of DHT in improving medication adherence and treatment outcomes in patients with TB.
METHODS
A literature search in PubMed and Cochrane databases was conducted. Randomized controlled trials (RCTs) that analyzed the effect of DHT interventions on medication adherence outcomes (treatment completion, treatment adherence, missed doses, and noncompleted rate) and treatment outcomes (cure rate and smear conversion) were included. Adult patients with either active or latent TB infection were included. The Jadad score was used for evaluating the study quality. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guideline was followed to report study findings.
RESULTS
In all, 16 RCTs were selected from 552 studies found, and 6 types of DHT interventions for TB were identified: 3 RCTs examined video directly observed therapy (VDOT), 1 examined video-observed therapy (VOT), 1 examined an ingestible sensor, 1 examined phone call reminders, 2 examined medication monitor boxes, and 8 examined SMS text message reminders. The outcomes used were treatment adherence, including treatment completion, treatment adherence, missed dose, and noncompleted rate, as well as clinical outcomes, including cure rate and smear conversion. In treatment completion, 4 RCTs (VDOT, VOT, ingestible sensor, SMS reminder) found significant effects, with odds ratios and relative risks (RRs) ranging from 1.10 to 7.69. Treatment adherence was increased in 1 study by SMS reminders (RR 1.05; 95% CI 1.04-1.06), and missed dose was reduced in 1 study by a medication monitor box (mean ratio 0.58; 95% CI 0.42-0.79). In contrast, 3 RCTs of VDOT and 3 RCTs of SMS reminders did not find significant effects for treatment completion. Moreover, no improvement was found in treatment adherence in 1 RCT of VDOT, missed dose in 1 RCT of SMS reminder, and noncompleted rate in 1 RCT of a monitor box, and 2 RCTs of SMS reminders. For clinical outcomes such as cure rate, 2 RCTs reported that phone calls (RR 1.30; 95% CI 1.07-1.59) and SMS reminders (OR 2.47; 95% CI 1.13-5.43) significantly affected cure rates. However, 3 RCTs found that SMS reminders did not have a significant impact on cure rate or smear conversion.
CONCLUSIONS
It was found that DHT interventions can be a promising approach. However, the interventions exhibited variable effects regarding effect direction and the extent of improving TB medication adherence and clinical outcomes. Developing DHT interventions with personalized feedback is required to have a consistent and beneficial effect on medication adherence and outcomes among patients with TB.
Topics: Adult; Biomedical Technology; Cell Phone; Humans; Medication Adherence; Randomized Controlled Trials as Topic; Reminder Systems; Text Messaging; Treatment Outcome; Tuberculosis
PubMed: 35195534
DOI: 10.2196/33062 -
Journal of Family Medicine and Primary... Sep 2022Melioidosis is a complex tropical disease linked with many complications. It is increasingly diagnosed in India. The clinical mimicry of this disease with several other... (Review)
Review
Melioidosis is a complex tropical disease linked with many complications. It is increasingly diagnosed in India. The clinical mimicry of this disease with several other common causes of pneumonia has kept the clinicians in ignorance. Usually, the diagnosis and appropriate management get delayed. The organism closely resembles the common contaminant Pseudomonas and is easily misidentified in microbiology laboratories. The diagnosis is often missed because of poor diagnostic sensitivity of blood culture, the gold standard of the diagnosis. All this contributes to increased morbidity and mortality. The rampant use of high-end broad-spectrum antibiotics like ceftazidime and meropenem at suboptimal dose and duration suppresses the diagnosis without eradicating the disease, leaving the chance of recurrence from its latency even after years. As an infectious disease, the cure and prevention depend on early diagnosis and treatment. An awareness of its peculiar presentations and history can differentiate clinically and suspect the condition much easily from other mimickers of tuberculosis to sepsis. Ultimately, the prevention of melioidosis remains the critical strategy. Increasing the number of cases and intricated management of this fatal but potentially curable disease had prompted us to take up the mission of preventing the disease by spreading knowledge and awareness.
PubMed: 36505663
DOI: 10.4103/jfmpc.jfmpc_1_22 -
Diabetes Technology & Therapeutics Oct 2020This observational study investigated whether the connected NovoPen 6 could influence insulin regimen management and glycemic control in people with type 1 diabetes... (Observational Study)
Observational Study
This observational study investigated whether the connected NovoPen 6 could influence insulin regimen management and glycemic control in people with type 1 diabetes (T1D) using a basal-bolus insulin regimen and continuous glucose monitoring in a real-world setting. Participants from 12 Swedish diabetes clinics downloaded pen data at each visit (final cohort: = 94). Outcomes included time in range (TIR; sensor glucose 3.9-10.0 mmol/L), time in hyperglycemia (>10 mmol/L), and hypoglycemia (L1: 3.0- <3.9 mmol/L; L2: <3.0 mmol/L). Missed bolus dose (MBD) injections were meals without bolus injection within -15 and +60 min from the start of a meal. Outcomes were compared between the baseline and follow-up periods (≥5 health care professional visits). Data were analyzed from the first 14 days following each visit. For the TIR and total insulin dose analyses ( = 94), a linear mixed model was used, and for the MBD analysis ( = 81), a mixed Poisson model was used. TIR significantly increased (+1.9 [0.8; 3.0] h/day; < 0.001) from baseline to follow-up period, with a corresponding reduction in time in hyperglycemia (-1.8 [-3.0; -0.6] h/day; = 0.003) and L2 hypoglycemia (-0.3 [-0.6; -0.1] h/day; = 0.005), and no change in time in L1 hypoglycemia. MBD injections decreased by 43% over the study ( = 0.002). Change in MBD injections corresponded to a decrease from 25% to 14% based on the assumption that participants had three main meals per day. Our study highlights the potential benefit on glycemic control and dosing behavior when reliable insulin dose data from a connected pen contribute to insulin management in people with T1D.
Topics: Blood Glucose; Blood Glucose Self-Monitoring; Diabetes Mellitus, Type 1; Humans; Hypoglycemic Agents; Injections, Subcutaneous; Insulin; Sweden
PubMed: 32003590
DOI: 10.1089/dia.2019.0411 -
Lancet (London, England) Sep 2020The anti-progesterone drug mifepristone and the prostaglandin misoprostol can be used to treat missed miscarriage. However, it is unclear whether a combination of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
The anti-progesterone drug mifepristone and the prostaglandin misoprostol can be used to treat missed miscarriage. However, it is unclear whether a combination of mifepristone and misoprostol is more effective than administering misoprostol alone. We investigated whether treatment with mifepristone plus misoprostol would result in a higher rate of completion of missed miscarriage compared with misoprostol alone.
METHODS
MifeMiso was a multicentre, double-blind, placebo-controlled, randomised trial in 28 UK hospitals. Women were eligible for enrolment if they were aged 16 years and older, diagnosed with a missed miscarriage by pelvic ultrasound scan in the first 14 weeks of pregnancy, chose to have medical management of miscarriage, and were willing and able to give informed consent. Participants were randomly assigned (1:1) to a single dose of oral mifepristone 200 mg or an oral placebo tablet, both followed by a single dose of vaginal, oral, or sublingual misoprostol 800 μg 2 days later. Randomisation was managed via a secure web-based randomisation program, with minimisation to balance study group assignments according to maternal age (<30 years vs ≥30 years), body-mass index (<35 kg/mvs ≥35 kg/m), previous parity (nulliparous women vs parous women), gestational age (<70 days vs ≥70 days), amount of bleeding (Pictorial Blood Assessment Chart score; ≤2 vs ≥3), and randomising centre. Participants, clinicians, pharmacists, trial nurses, and midwives were masked to study group assignment throughout the trial. The primary outcome was failure to spontaneously pass the gestational sac within 7 days after random assignment. Primary analyses were done according to intention-to-treat principles. The trial is registered with the ISRCTN registry, ISRCTN17405024.
FINDINGS
Between Oct 3, 2017, and July 22, 2019, 2595 women were identified as being eligible for the MifeMiso trial. 711 women were randomly assigned to receive either mifepristone and misoprostol (357 women) or placebo and misoprostol (354 women). 696 (98%) of 711 women had available data for the primary outcome. 59 (17%) of 348 women in the mifepristone plus misoprostol group did not pass the gestational sac spontaneously within 7 days versus 82 (24%) of 348 women in the placebo plus misoprostol group (risk ratio [RR] 0·73, 95% CI 0·54-0·99; p=0·043). 62 (17%) of 355 women in the mifepristone plus misoprostol group required surgical intervention to complete the miscarriage versus 87 (25%) of 353 women in the placebo plus misoprostol group (0·71, 0·53-0·95; p=0·021). We found no difference in incidence of adverse events between the study groups.
INTERPRETATION
Treatment with mifepristone plus misoprostol was more effective than misoprostol alone in the management of missed miscarriage. Women with missed miscarriage should be offered mifepristone pretreatment before misoprostol to increase the chance of successful miscarriage management, while reducing the need for miscarriage surgery.
FUNDING
UK National Institute for Health Research Health Technology Assessment Programme.
Topics: Abortion, Missed; Adult; Double-Blind Method; Drug Therapy, Combination; Humans; Mifepristone; Misoprostol; Oxytocics; Treatment Outcome
PubMed: 32853559
DOI: 10.1016/S0140-6736(20)31788-8 -
JAMA Network Open Apr 2023Bayesian clinical trial designs are increasingly common; given their promotion by the US Food and Drug Administration, the future use of the bayesian approach will only... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Bayesian clinical trial designs are increasingly common; given their promotion by the US Food and Drug Administration, the future use of the bayesian approach will only continue to increase. Innovations possible when using the bayesian approach improve the efficiency of drug development and the accuracy of clinical trials, especially in the context of substantial data missingness.
OBJECTIVE
To explain the foundations, interpretations, and scientific justification of the bayesian approach in the setting of lecanemab trial 201, a bayesian-designed phase 2 dose-finding trial; to demonstrate the efficiency of using a bayesian design; and to show how it accommodates innovations in the prospective design and also treatment-dependent types of missing data.
DESIGN, SETTING, AND PARTICIPANTS
This study was a bayesian analysis of a clinical trial comparing the efficacy of 5 lecanemab 201 dosages for treatment of early Alzheimer disease. The goal of the lecanemab 201 trial was to identify the effective dose 90 (ED90), the dose achieving at least 90% of the maximum effectiveness of doses considered in the trial. This study assessed the bayesian adaptive randomization used, in which patients were preferentially assigned to doses that would give more information about the ED90 and its efficacy.
INTERVENTIONS
Patients in the lecanemab 201 trial were adaptively randomized to 1 of 5 dose regimens or placebo.
MAIN OUTCOMES AND MEASURES
The primary end point of lecanemab 201 was the Alzheimer Disease Composite Clinical Score (ADCOMS) at 12 months with continued treatment and follow-up out to 18 months.
RESULTS
A total 854 patients were included in trial treatment: 238 were in the placebo group (median age, 72 years [range, 50-89 years]; 137 female [58%]) and 587 were assigned to a lecanemab 201 treatment group (median age, 72 years [range, 50-90 years]; 272 female [46%]). The bayesian approach improved the efficiency of a clinical trial by prospectively adapting to the trial's interim results. By the trial's end more patients had been assigned to the better-performing doses: 253 (30%) and 161 (19%) patients to 10 mg/kg monthly and 10 mg/kg biweekly vs 51 (6%), 52 (6%), and 92 (11%) patients to 5 mg/kg monthly, 2.5 mg/kg biweekly, and 5 mg/kg biweekly, respectively. The trial identified 10 mg/kg biweekly as the ED90. The change in ADCOMS of the ED90 vs placebo was -0.037 at 12 months and -0.047 at 18 months. The bayesian posterior probability that the ED90 was superior to placebo was 97.5% at 12 months and 97.7% at 18 months. The respective probabilities of super-superiority were 63.8% and 76.0%. The primary analysis of the randomized bayesian lecanemab 201 trial found in the context of missing data that the most effective dose of lecanemab nearly doubles its estimated efficacy at 18 months of follow-up in comparison with restricting analysis to patients who completed the full 18 months of the trial.
CONCLUSIONS AND RELEVANCE
Innovations associated with the bayesian approach can improve the efficiency of drug development and the accuracy of clinical trials, even in the context of substantial data missingness.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01767311.
Topics: Humans; Female; Aged; Bayes Theorem; Alzheimer Disease
PubMed: 37040116
DOI: 10.1001/jamanetworkopen.2023.7230 -
EClinicalMedicine May 2023Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) is a single-tablet regimen recommended for HIV-1 treatment. The safety and efficacy of B/F/TAF as initial...
BACKGROUND
Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) is a single-tablet regimen recommended for HIV-1 treatment. The safety and efficacy of B/F/TAF as initial therapy was established in two Phase 3 studies: 1489 (vs dolutegravir [DTG]/abacavir/lamivudine) and 1490 (vs DTG + F/TAF). After 144 weeks of randomized follow-up, an open-label extension evaluated B/F/TAF to 240 weeks.
METHODS
Of 634 participants randomized to B/F/TAF, 519 completed the double-blinded treatment, and 506/634 (80%) chose the 96-week open-label B/F/TAF extension, which was completed by 444/506 (88%) participants. Efficacy was based on the secondary outcome of the proportion of participants with HIV-1 RNA <50 copies/mL at Week 240 by missing = excluded and missing = failure methods. All 634 participants who were randomized to B/F/TAF and received at least one dose of B/F/TAF were included in efficacy and safety analyses. (Study 1489: ClinicalTrials.govNCT02607930; EudraCT 2015-004024-54. Study 1490: ClinicalTrials.govNCT02607956; EudraCT 2015-003988-10).
FINDINGS
Of those with available virologic data, 98.6% (95% CI [97.0%-99.5%], 426/432) maintained HIV-1 RNA <50 copies/mL at Week 240 (missing = excluded); when missing virologic data were considered as failure, 67.2% (95% CI [63.4%-70.8%], 426/634) maintained HIV-1 RNA <50 copies/mL. Mean (SD) change in CD4+ count from baseline was +338 (236.2) cells/μL. No treatment-emergent resistance to B/F/TAF was detected. Adverse events led to drug discontinuation in 1.6% (n = 10/634) of participants (n = 5 with events considered drug-related). No discontinuations were due to renal adverse events. Median (IQR) total cholesterol increased 21 (1,42) mg/dL from baseline; the change in total cholesterol:HDL was 0.1 (-0.5,0.6) Median (IQR) weight change from baseline was +6.1 kg (2.0, 11.7) at Week 240. In Study 1489, hip and spine bone mineral density mean percent changes from baseline were ≤0.6%.
INTERPRETATION
Through 5 years of follow-up, B/F/TAF maintained high rates of virologic suppression with no treatment-emergent resistance and rare drug discontinuations due to adverse events. These results demonstrate the durability and safety of B/F/TAF in people with HIV.
FUNDING
Gilead Sciences.
PubMed: 37200995
DOI: 10.1016/j.eclinm.2023.101991 -
MMWR. Morbidity and Mortality Weekly... Nov 2022In 2020, the World Health Assembly endorsed the Immunization Agenda 2030, an ambitious global immunization strategy to reduce morbidity and mortality from...
In 2020, the World Health Assembly endorsed the Immunization Agenda 2030, an ambitious global immunization strategy to reduce morbidity and mortality from vaccine-preventable diseases (1). This report updates a 2020 report (2) with global, regional,* and national vaccination coverage estimates and trends through 2021. Global estimates of coverage with 3 doses of diphtheria-tetanus-pertussis-containing vaccine (DTPcv3) decreased from an average of 86% during 2015-2019 to 83% in 2020 and 81% in 2021. Worldwide in 2021, 25.0 million infants (19% of the target population) were not vaccinated with DTPcv3, 2.1 million more than in 2020 and 5.9 million more than in 2019. In 2021, the number of infants who did not receive any DTPcv dose by age 12 months (18.2 million) was 37% higher than in 2019 (13.3 million). Coverage with the first dose of measles-containing vaccine (MCV1) decreased from an average of 85% during 2015-2019 to 84% in 2020 and 81% in 2021. These are the lowest coverage levels for DTPcv3 and MCV1 since 2008. Global coverage estimates were also lower in 2021 than in 2020 and 2019 for bacillus Calmette-Guérin vaccine (BCG) as well as for the completed series of Haemophilus influenzae type b vaccine (Hib), hepatitis B vaccine (HepB), polio vaccine (Pol), and rubella-containing vaccine (RCV). The COVID-19 pandemic has resulted in disruptions to routine immunization services worldwide. Full recovery to immunization programs will require context-specific strategies to address immunization gaps by catching up missed children, prioritizing essential health services, and strengthening immunization programs to prevent outbreaks (3).
Topics: Infant; Child; Humans; Vaccination Coverage; Pandemics; COVID-19; Diphtheria-Tetanus-Pertussis Vaccine; Immunization Programs; Vaccination; Measles Vaccine; Rubella Vaccine; Immunization Schedule
PubMed: 36327156
DOI: 10.15585/mmwr.mm7144a2